This invention relates to a delivery system for delivering macromolecular active agents (molecular weight greater than about 1300) at a controlled rate for a prolonged period of time. More specifically, it relates to a cholesteric matrix permeable to the passage by diffusion of the macromolecular active agents contained therein.
Diffusional active agent delivery systems comprising an active agent dispersed in a matrix that is permeable to the active agent are well known. The active agent is released from such systems by diffusing through the matrix at a controlled rate in accordance with Fick's Law. In the majority of these systems, the matrix is a synthetic polymer. U.S. Pat. Nos. 3,903,880; 4,069,307; and 4,016,251 assigned to the Alza Corporation disclose active agent delivery systems comprising a matrix of an ethylene vinyl acetate copolymer, wherein the mechanism of release of the active agent is diffusion. Cholesterol has also been used to form diffusional matrix delivery systems. For example, Kincl, et al in "Sustained Release Hormonal Preparation," ACTA Endocrinologica, 64, 256-264 (1970) disclosed cholesterol pellet implants that released progesterone, and Kent, et al in "The Use of a Cholesterol Matrix Pellet Implant for Early Studies on the Prolonged Release in Animals of Agonist Analogues of Luteinizing Hormone-Releasing Hormone," 7th Int. Sump. Controlled Release of Bioactive Materials, Fort Lauderdale, Fla., 1980, disclosed the use of a cholesterol matrix similar to the matrix of this invention, for the delivery of luteinizing hormone releasing hormone (LHRH) analogues.
The polymeric matrix delivery systems and the monolithic cholesterol matrix delivery systems known in the art work well for the sustained delivery of small molecules such as steroids and most antibiotics. However, the use of diffusional matrices for prolonged delivery of active agents has heretofore been limited to agents of relatively low molecular weight. No diffusional matrix delivery system has previously been known which is suitable for the prolonged release of macromolecules, particularly those whose molecular weight exceeds about 1300. Matrix delivery systems have in fact heretofore proven incapable of delivering large molecules at useful rates, due to the extremely low diffusivity of these molecules in known matrix materials. A possible exception are the polymeric matrix delivery systems disclosed in U.S. Pat. No. 4,164,560 to Folkman and Langer. However, the systems of that patent do not appear to operate by simple diffusion, and have an extremely uneven release rate profile.
There is a need for a biocompatible delivery system capable of prolonged administration of macromolecules to an appropriate body site. The utility of a wide variety of the macromolecular active agents presently of interest for applications in medicine and animal husbandry, is diminished by their short biological half lives, and the consequent necessity of frequent administration. In addition, many of these compounds have extremely low oral activity, and must be administered by injection.